Abstract

The pursuit of multi-targeted therapies that simultaneously address mucosal immune dysregulation, barrier dysfunction and gut microbiota imbalance in ulcerative colitis (UC) remains a major challenge. Astragalin, a natural flavonoid, represents a promising therapeutic candidate, yet its mechanisms of action have remained poorly defined. Here, we used an integrated deep-learning platform that combines multiple neural architectures to predict a high-confidence target of Astragalin, and then validated these predictions in a DSS-induced murine colitis model using pharmacological assays, 16S rRNA sequencing, untargeted metabolomics and complementary cellular studies. Our framework identified formyl peptide receptor 1 (FPR1) as a high-confidence target, and we show that Astragalin directly binds to FPR1, promotes its degradation through a proteasome-dependent pathway and consequently inhibits NF-κB activation. Consistent with this mechanism, Astragalin ameliorated colitis symptoms, suppressed pro-inflammatory cytokines and enhanced intestinal barrier integrity. Beyond host signalling, Astragalin restored gut microbial ecology, notably enriching Akkermansia muciniphila, and reversed colitis-associated metabolic disturbances, with prominent effects on glutathione and L-ascorbate metabolism. Correlation analyses further revealed a strong positive association between A. muciniphila abundance and key protective metabolites. Together, these findings uncover Astragalin as a natural FPR1 inhibitor that alleviates colitis through a self-reinforcing circuit involving targeted protein degradation, suppression of inflammation, restoration of a beneficial microbiota and reinforcement of the mucosal barrier, positioning Astragalin as a multi-faceted therapeutic strategy for UC..